EP1740572A1 - Nouveaux composes d'alcyne a effet antagoniste vis-a-vis de mch et medicaments contenant ces composes - Google Patents

Nouveaux composes d'alcyne a effet antagoniste vis-a-vis de mch et medicaments contenant ces composes

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Publication number
EP1740572A1
EP1740572A1 EP05716558A EP05716558A EP1740572A1 EP 1740572 A1 EP1740572 A1 EP 1740572A1 EP 05716558 A EP05716558 A EP 05716558A EP 05716558 A EP05716558 A EP 05716558A EP 1740572 A1 EP1740572 A1 EP 1740572A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
phenyl
group
hydroxy
cycloalkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP05716558A
Other languages
German (de)
English (en)
Inventor
Dirk Stenkamp
Stephan Georg Mueller
Philipp Lustenberger
Thorsten Lehmann-Lintz
Leo Thomas
Marcus Schindler
Gerald Jürgen ROTH
Klaus Rudolf
Ralf R. H. Lotz
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
Original Assignee
Boehringer Ingelheim International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
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Filing date
Publication date
Family has litigation
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Application filed by Boehringer Ingelheim International GmbH, Boehringer Ingelheim Pharma GmbH and Co KG filed Critical Boehringer Ingelheim International GmbH
Publication of EP1740572A1 publication Critical patent/EP1740572A1/fr
Withdrawn legal-status Critical Current

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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/61—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • New alkyne compounds having MGH antagonist activity and medicaments containing these compounds are described in detail below.
  • the present invention relates to novel alkyne compounds, their physiologically acceptable salts and their use as MCH antagonists and their use for the preparation of a medicament which is used for the prophylaxis and / or treatment of phenomena and / or diseases caused by MCH or with MCH are in a different causal relationship, is appropriate.
  • Another object of this invention relates to the use of a compound of the invention for influencing the eating behavior and for reducing body weight and / or for preventing an increase in 'body weight of a mammal.
  • compositions and pharmaceutical compositions, each containing a compound of the invention, as well as processes for their preparation are the subject of this invention. Further objects of this invention relate to processes for the preparation of the compounds according to the invention.
  • obesity refers to an excess of adipose tissue in the body.
  • obesity is basically considered to be any elevated level of body fat, leading to a health risk.
  • BMI body mass index
  • the individuals having a body mass index (BMI) defined as the kilogram of body weight divided by height (in meters) squared are above the value of 25, especially above 30, when considered suffering from obesity.
  • MCH antagonists inter alia WO 01/21577, WO 01/82925.
  • MCH Melanin-concentrating hormone
  • the MCH-1 R antagonist SNAP-7941 provides further anxiolytic and antidepressant effects in behavioral experiments with rats [3].
  • the MCH-MCH-1 R system is involved not only in the regulation of the energy balance but also the affectivity.
  • WO 01/82925 also compounds of the formula in which Ar 1 is a cyclic group, X and Y spacer groups, Ar is an optionally substituted condensed polycyclic aromatic ring, R 1 and R 2 are independently H or a hydrocarbon group, wherein R 1 and R 2 together with the adjacent N Atom can form an N-containing heterocyclic ring and R 2 together with the adjacent N-atom and Y can form an N-containing hetero ring, described as MCH antagonists for the treatment of, inter alia, obesity.
  • Y, A and B may denote cyclic groups and X, Z and W may represent bridges or bonds, as MCH antagonists.
  • Y, A and B may denote cyclic groups and X, Z and W may represent bridges or bonds, as MCH antagonists.
  • Y, A and B may denote cyclic groups and X, Z and W may represent bridges or bonds, as MCH antagonists.
  • WO 04/039764 A1 discloses amide compounds of the formula I.
  • the present invention has for its object to show new alkyne compounds, especially those which have a particularly high activity as MCH antagonists. It is also an object of this invention to provide novel alkyne compounds which allow to influence mammalian eating habits and, in particular in mammals, to achieve a reduction in body weight and / or to prevent an increase in body weight.
  • Further objects of the present invention relate to the demonstration of advantageous uses of the compounds of the invention. It is also an object of this invention to provide a process for the preparation of the alkyne compounds of the present invention. Further objects of the present invention result for the skilled person directly from the preceding and following statements.
  • a first subject of the present invention are alkyne compounds of general formula I.
  • R 1 C 3 . 6 -alkenyl, C 3 . 6 alkynyl, (hydroxy-Cs- T -cycloalkyO-Ci-js-alkyl, oxa-C 4 - 7 - cycloalkyl, dihydroxy-C 3, 7 -alkyl, where the anussiben groups may be mono- or polysubstituted with substituents independently selected from the group consisting of halogen, hydroxy, cyano, C ⁇ alkyl, C 3 7 cycloalkyl, C 3 -.
  • R 2 has, independently of R 1, one of the meanings given above for R 1 or R 2 has one meaning from the group consisting of H, C ⁇ . 8- alkyl, C 3 . 7 -cycloalkyl or an optionally with the same or different radicals R 20 mono- or polysubstituted and / or with nitro monosubstituted phenyl or pyridinyl, wherein the alkyl or cycloalkyl group with the same or different radicals R 11 are mono- or polysubstituted and wherein a -CH 2 group in position 3 or 4 of a 5, 6 or 7-membered cycloalkyl group may be replaced by -O-, -S- or -NR 13 -, or the radicals R 1 , R 2 together with the N-atom to which they are attached form a heterocyclic group which is selected from the meanings - dihydroxy-cyclo-C 4 .
  • alkyl, alkoxy, Cylcoalkyl groups may have one or more identical or different substituents selected from halogen and hydroxy;
  • W, Z independently of one another are a single bond or a C 1-6 -alkylene bridge, wherein carbon atoms may be joined together with an additional C ⁇ alkylene bridge, two adjacent, and where one or two C atoms independently of one another by one or two identical or different d-3 alkyl residues can be substituted with two Alkyl radicals may be joined together to form a carbocyclic ring, and
  • Y, A are independently selected from the group of. bivalent cyclic groups phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, naphthyl, tetrahydronaphthyl, indolyl, dihydroindolyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, isoquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, benzimidazolyl, benzoxazolyl, chromanyl, chromene-4-onyl, thienyl, Furanyl, benzothienyl or benzofuranyl, said cyclic groups one or more times to one or more C atoms having the same or different radicals R 20 , in the case of a phenyl ring also additionally simply with nitro, and / or one or more
  • B is one of the meanings given for Y, A or
  • Cy is a carbo or heterocyclic group selected from one of the following meanings - a saturated 3- to 7-membered carbocyclic group, - an unsaturated 4- to 7-membered carbocyclic group, - a phenyl group, a saturated 4- to 7-membered or unsaturated 5- to 7-membered heterocyclic group having an N, O or S atom as a heteroatom, - a saturated or unsaturated 5- to 7-membered heterocyclic group having two or more N atoms or with one or two N atoms and one O or S atom as heteroatoms, - an aromatic heterocyclic 5- or 6-membered group with one or more identical or different heteroatoms selected from N, O and / or S.
  • R 4 is H, C 1-4 -alkyl, C 3 . 7 -cycloalkyl or C 1 -C 6 -cycloalkyl-ds-alkyl,
  • R 10 is hydroxy, ⁇ -hydroxy-C- ,. 3 -alkyl
  • R 11 is halogen, C 1-4 -alkyl, C 2 . 6 -alkenyl, C 2 - 6 alkynyl, R 15 -O-, R 15 -O-CO-, R 15 -CO- O-, cyano, R 16 R 17 N-, R 18 R 19 N-CO- or Cy, wherein, in the above-mentioned groups one or more C atoms independently of one another by substituents selected from halogen, OH, CN, CF 3, C- ⁇ - 3 -alkyl, hydroxy-C- ⁇ - 3 alkyl mono- or may be substituted several times;
  • R 13 is one of the meanings given for R 17 .
  • R 15 is H, d-4 alkyl, C 3rd 7 -cycloalkyl, C 1 -C 4 -alkyl-C 1 -C 5 -alkyl, phenyl, phenyl-C 1 -C 3 -alkyl, pyridinyl or pyridinyl-C 1 -C 3 -alkyl, R 16 is H, C 1 -alkyl-AI, C 3 . 7 cycloalkyl, C 3-7 cycloalkyl-d- 3 -alkyl, C. 4 7 cycloalkenyl, C 4 .
  • R 17 one of the meanings for R 16 or phenyl specified, phenyl-d- C3 alkyl, pyridinyl, d- alkylcarbonyl, hydroxycarbonyl-d-3-alkyl, C ⁇ - alkoxycarbonyl, C ⁇ C ⁇ alkoxycarbonyl-s- alkyl.d ⁇ -alkylcarbonylamino-C M-alkyl, N- (C 1-4 -AIkylcarbonyl) -N- (C 1-4 -alkyl) -amino-C 2 - 3 alkyl, C ⁇ alkylsulfonyl, d- Alkylsulfonylamino-C 2 . 3 -alkyl or N- (C 1 4 alkylsulfonyl.) -N (-C 1-4 alkyl) amino-C 2 - 3 alkyl;
  • R 18, R 19 are independently H or C ⁇ - 6 alkyl
  • R 20 is halogen, hydroxy, cyano, de-alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 3 - 7 - cycloalkyl, C 3 - 7 cycloalkyl-d-C3 alkyl, hydroxy-d- 3 alkyl, R -d- 3 alkyl, or one of the meanings given for R 22,
  • R 21 is C 1-4 -alkyl, ⁇ -hydroxy-C 2 . 6 -alkyl, ⁇ -C- 4- alkoxy-C 2 . 6 -alkyl, ⁇ -d-alkyl-amino-C 2 - 6 -alkyl, ⁇ -di- (C 1 - 4 -alkyl) -amino-C 2 . 6 -alkyl, ⁇ -cyclo-C 3 .
  • kyl) aminocarbonyl cyclo -C 3 - 6 alkyl-amino-carbonyl, cyclo-C. 3 6 -alkylenimino-carbonyl, phenylaminocarbonyl, cyclo-Cs-e-alkylenimino-C ⁇ -alkyl-aminocarbonyl, C- 4- alkyl-sulfonyl, C ⁇ -alkyl-sulfinyl, C ⁇ -alkyl-sulfonylamino, amino, C.
  • the compounds according to the present invention have in comparison to known, structurally comparable Compounds have a particular effect as antagonists of the MCH receptor, in particular the MCH-1 receptor, and show very good affinities in MCH receptor binding studies.
  • the compounds of the invention have a high to very high selectivity with respect to the MCH receptor.
  • the compounds according to the invention have low toxicity, good oral absorbability and intracerebral transitivity, in particular cerebral activity.
  • the invention also relates to the respective compounds in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates, in the form of tautomers and in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acids. Also included in the subject matter of this invention are the compounds of the invention, including their salts, in which one or more hydrogen atoms are replaced by deuterium.
  • physiologically acceptable salts of the alkyne compounds according to the invention described above and below are also an object of this invention.
  • compositions comprising at least one alkyne compound according to the invention and / or a salt according to the invention in addition to optionally one or more physiologically acceptable excipients.
  • medicaments comprising at least one alkyne compound according to the invention and / or an inventive salt in addition to optionally one or more inert carriers and / or diluents are the subject of the present invention.
  • an object of this invention is the use of at least one alkyne compound according to the invention and / or a salt according to the invention for influencing the eating behavior of a mammal.
  • At least one alkyne compound of the invention and / or a salt according to the invention for reducing body weight and / or preventing an increase in body weight of a mammal is an object of this invention.
  • an object of the present invention is the use of at least one alkyne compound according to the invention and / or a salt according to the invention for the production of a medicament with MCH receptor antagonistic activity, in particular with MCH-1 receptor antagonistic activity.
  • an object of this invention is the use of at least one alkyne compound according to the invention and / or a salt according to the invention for the preparation of a medicament, which for the prophylaxis and / or treatment of phenomena and / or diseases caused by MCH or with MCH in one other causal relationship is appropriate.
  • Another object of this invention is the use of at least one alkyne compound according to the invention and / or a salt according to the invention for the manufacture of a medicament, which for the prophylaxis and / or treatment of metabolic disorders and / or eating disorders, in particular obesity, bulimia, bulimia nervosa, cachexia , Anorexia, anorexia nervosa and hyperphagia, is suitable.
  • an object of this invention is the use of at least one alkyne compound according to the invention and / or a salt according to the invention for the preparation of a medicament which is used for the prophylaxis and / or treatment of obesity-related diseases and / or disorders, in particular diabetes, especially type II Diabetes, diabetic complications, including diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, pathological glucose tolerance, encephalorrhagia, cardiac insufficiency, cardiovascular diseases, especially arteriosclerosis and hypertension, arthritis and gonitis.
  • diabetes especially type II Diabetes, diabetic complications, including diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, pathological glucose tolerance, encephalorrhagia, cardiac insufficiency, cardiovascular diseases, especially arteriosclerosis and hypertension, arthritis and gonitis.
  • the present invention has the use of at least one alkyne compound according to the invention and / or a salt according to the invention for the manufacture of a medicament which is used for the prophylaxis and / or treatment of
  • the subject of the study is hyperlipidemia, cellulitis, fat accumulation, malignant mastocytosis, systemic mastocytosis, emotional disorders, affective disorders, depression, anxiety, sleep disorders, reproductive disorders, sexual disorders, memory disorders, epilepsy, forms of dementia and hormonal disorders.
  • a further subject of this invention is the use of at least one alkyne compound according to the invention and / or a salt according to the invention for the preparation of a medicament which is suitable for the prophylaxis and / or treatment of voiding disorders such as urinary incontinence, overactive bladder, urinary urgency, nocturia and enuresis ,
  • the subject of the present invention is the use of at least one alkyne compound according to the invention and / or a salt according to the invention for the production of a medicament which is suitable for the prophylaxis and / or treatment of dependencies and / or withdrawal symptoms.
  • an object of this invention relates to processes for the preparation of a medicament according to the invention, characterized in that at least one alkyne compound according to the invention and / or a salt according to the invention is incorporated into one or more inert carriers and / or diluents by non-chemical means.
  • a further subject of this invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a first active ingredient selected from the alkyne compounds and / or the corresponding salts, and a second active ingredient selected from the group consisting of active ingredients for the treatment of diabetes, drugs for the treatment of diabetic complications, drugs for the treatment of obesity, preferably other than MCH antagonists, drugs for the treatment of hypertension, drugs for the treatment of Dyslipidemia or Hyperlipidemia, including arteriosclerosis, drugs for the treatment of arthritis, drugs for
  • Treatment of anxiety and drugs for the treatment of depression optionally with one or more inert carriers and / or diluents.
  • an object of this invention relates to a process for the preparation of alkyne compounds of the formula A.5
  • R 1 , R 2 , X, Y, W, A and B have one of the meanings given above and below, in which a halogen compound of the formula A.1
  • Hal is chlorine, bromine or iodine, preferably bromine or iodine, with an alkyne compound of the formula A.2
  • Another object of this invention is a process for the preparation of alkyne compounds of formula B.5
  • R 1 , R 2 , X, Y, Z, A and B have one of the meanings given above and below,
  • Hal is chlorine, bromine or iodine, preferably bromine or iodine, with an alkyne compound of the formula B.2
  • an object of this invention relates to a process for the preparation of alkyne compounds of the formula C.3
  • R 1 , R 2 , -X, Y, W, A and B have one of the meanings given above and below,
  • Hal is chlorine, bromine or iodine, preferably bromine or iodine, with an alkyne compound of the formula C.2
  • Another object of this invention is a process for the preparation of alkyne compounds of the formula D.3
  • R 1 , R 2 , X, Y, Z, A and B have one of the meanings given above and below,
  • Hal is chlorine, bromine or iodine, preferably bromine or iodine, with an alkyne compound of the formula D.1
  • radicals and / or substituents in a compound may each have the same or different meanings given.
  • the radical R 1 is selected from the group of meanings C 3 . 6 alkenyl, C 3 . 6- alkynyl, (hydroxy-C 3 - 7 -cycloalkyl) -C ⁇ 3 -alkyl, oxa-C 5 . 7 - cycloalkyl, dihydroxy-C 3 . 7 -alkyl, wherein the anussiben groups may be mono- or polysubstituted with substituents which are independently selected from the group consisting of halogen, hydroxy, cyano, d- 4 alkyl, C 3 . 7 -cycloalkyl, C 3 .
  • R 1 preferred meanings of the group R 1 are C 3-5 alk-2-enyl, C. 3 5- alk-2-ynyl, (1-hydroxy-C 3 - 6 -cycloalkyl) -C ⁇ . 3- alkyl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, dihydroxy-C 3 - 5 -alkyl, wherein the anussiben groups may be mono- or polysubstituted as previously indicated.
  • preferred substituents are independently fluorine, chlorine, bromine, hydroxy, cyano, CF 3, d ⁇ alkyl, C 3 _ 7 cycloalkyl, C 3 - 7 - cycloalkyl C ⁇ - 3 alkyl, d- 4 -alkoxy-C.
  • substituents independently of one another are fluorine, chlorine, hydroxyl, cyano, CF 3 , hydroxymethyl, hydroxyethyl, C 1-4 -alkyl, C 3 . 6 cycloalkyl, C 3 - 6 cycloalkyl-methyl, d-jrAlkoxy-ds-alkyl, d-3 alkoxy, amino, C ⁇ - 3 -alkyl-amino and di- amino (C 1 3 alkyl.).
  • R 1 is prop-2-enyl, but-2-enyl, prop-2-ynyl, but-2-ynyl, (1-hydroxy-C 3 - 6 cycloalkyl) -methyl, Tetrahydropyran-3-yl, tetrahydropyran-4-yl, 2,3-dihydroxy-C 3 - 5 -alkyl.
  • R 2 independently of R 1 has one of the meanings given above for R 1 or R 2 has one meaning from the group consisting of H, ds-alkyl, C 3 . 7 -cycloalkyl or an optionally substituted by the radical R 20 mono- or polysubstituted and / or with nitro monosubstituted phenyl or pyridinyl, wherein the alkyl or cycloalkyl group independently of one another with the same or different radicals R 11 mono- or polysubstituted and wherein a -CH 2 group in position 3 or 4 of a 5, 6 or 7-membered cycloalkyl group may be replaced by -O-, -S- or -NR 13 -.
  • R 11 in this case F, Cl, Br, d-6 alkyl, C 2 - 6 alkenyl, C. 2 6 - alkynyl, R 15 -O-, cyano, R 16 R 17 N-, C 3 - 7 cycloalkyl, cyclo-C 3 - 6 -alkylenimino-, pyrrolidinyl, N- (d- alkyl) -pyrrolidinyl, piperidinyl, N- (C 1 - 4 alkyl) -piperidinyl, phenyl and pyridyl, wherein in the above-mentioned groups and radicals one or more C-atoms one or more times by F independently of one another, C
  • R 11 has one of the meanings R 15 -O-, cyano, R 16 R 17 N- or cyclo-C 3 - 6 -alkyleneimino-, preferably the R 11 -substituted carbon atom of the alkyl or cycloalkyl group is not directly linked to a heteroatom such as the -NX- group.
  • the radical R 2 is H, d-6 alkyl, C 3rd 5 alkenyl, C 3 - 5 alkynyl, C 3 . 7 -cycloalkyl, hydroxy-C 3 . 7 -cycloalkyl, C 3-7 -cycloalkyl-C ⁇ - -alkyl 3, (.
  • Preferred substituents of the above-mentioned phenyl or pyridyl are selected from the group F, Cl, Br, I, cyano, d-4 alkyl, d- 4 alkoxy, difluoromethyl, trifluoromethyl, hydroxy, amino, d 3- alkylamino, di ( 3- alkyl) -amino, acetylamino, aminocarbonyl,
  • Particularly preferred meanings of the group R 2 are selected from the group consisting of H, d- C4 alkyl, C 3-5 alkenyl, C 3-5 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl d- 3 - alkyl, ⁇ - (. C 1 4 alkoxy) -C 2.
  • radicals R 2 are selected from the group consisting of H, methyl, ethyl, n-propyl, i-propyl, prop-2-enyl, prop-2-ynyl, 2-methoxyethyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopentylmethyl , (1-Hydroxy-cyclopropyl) -methyl, 2-hydroxyethyl, 3-hydroxypropyl, benzyl and pyridyl.
  • the radicals R 1, R 2 form together with the N-atom to which they are bonded, a heterocyclic group selected from the meanings dihydroxy- (cyclo-C. 4 7 -alkylene-imino), (Hydroxy-d- 4- alkyl) -hydroxy-cyclo-C 3 - alkylene-imino, (hydroxy-d- 3- aikyl) -cyclo-C 3 .
  • the C 1 - 3 - alkyl group may be substituted by one or more identical or different C ⁇ -alkyl groups, of which 2 alkyl groups to form a C 3 - 7 -Cyloalkyl- Group can be connected; wherein the heterocyclic groups mentioned may be mono- or polysubstituted with substituents independently selected from the group consisting of halogen, hydroxy, cyano, d-4 alkyl, C 3rd 7 -cycloalkyl, d-cycloalkyl-ds-alkyl, d- - alkoxy-C ⁇ -alkyl, d- 4 -alkoxy, C ⁇ -alkenyl, C 2 - 4 -alkynyl, amino, d- 4- alkyl-amino and di- (C 1 - 4 - alkyl) -amino, wherein occurring in the said substituents al
  • preferred heterocyclic groups are 3,4-dihydroxypyrrolidinyl, 3,4-dihydroxypiperidinyl, 3,5-dihydroxypiperidinyl, (hydroxy-d- 3- alkyl) -hydroxypyrrolidinyl, (hydroxy-d- 3- alkyl) -hydroxy- piperidinyl, (hydroxy-C 3 6 cycloalkyl.) - hydroxypyrrolidinyl, (hydroxy C 3 - 6 cycloalkyl) -hydroxy-piperidinyl, (ds alkyl-hydroxy-methyl) - pyrrolidinyl, (ds alkyl-hydroxy-methyl- -piperidinyl, (di-ds-alkyl-hydroxy-methyl-pyrrolidinyl, (di-C 1 -C 6 -alkyl-hydroxy-methyl-1-piperidinyl, (1-hydroxy-C 3 - 6 -cycloalkyl) -pyrrolidinyl, (1-hydroxy-hydroxy-C 3
  • the H atom can also be replaced by a methyl group in one or two hydroxyl groups.
  • Preferred substituents of said heterocyclic groups are fluorine, chlorine, hydroxyl, CF 3 , C ⁇ . 3- alkyl and hydroxy-d-alkyl, in particular methyl, ethyl and CF 3 .
  • heterocyclic groups are 3,4-dihydroxypyrrolidinyl, 3,4-dihydroxypiperidinyl, 3,5-dihydroxypiperidinyl, (hydroxymethyl) -hydroxy-pyrrolidinyl, (hydroxymethyl) -hydroxy-piperidinyl, (1-hydroxyethyl) -hydroxy -pyrrolidinyl, (1-hydroxyethyl) -hydroxy-piperidinyl, (1-hydroxy-1-methylethyl) -hydroxy-pyrrolidinyl, (1-hydroxy-1-methylethyl) -hydroxy-piperidinyl, (1-hydroxycyclopropyl) -hydroxy-pyrrolidinyl , (1-Hydroxycyclopropyl) -hydroxy-piperidinyl, (1-hydroxy-cyclopropyl) -pyrrolidinyl, (1-hydroxy-cyclopropyl) -piperidinyl, (1-hydroxyethyl) -pyrrolidinyl, (1-hydroxyeth
  • methyl or ethyl groups may be mono-, di- or trisubstituted by fluorine, and in which one or more carbon-bonded hydrogen atoms of the heterocycle formed by the group R 1 R 2 N- independently of one another by fluorine, chlorine, CN, CF 3 , D 3 -alkyl, hydroxy-D 3 -alkyl, especially D 3 -alkyl or CF 3 , preferably methyl, ethyl, CF 3 are substituted.
  • the group X is preferably a C 2 --Alkylen- bridge, more preferably ethylene or propylene, wherein one or two C atoms simply with hydroxy, hydroxy-C- ⁇ - 3 -alkyl or d. 3 alkoxy, in particular hydroxy, may be substituted, and wherein the alkylene bridge with C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 3 - 6 cycloalkyl, or C.
  • 3 6 -cycloalkyl-C 1-3 -alkyl may be monosubstituted, disubstituted or trisubstituted by identical or different C 1-3 -alkyl groups, and membered cycloalkyl group or an alkyl group and an alkenyl group to form a 5 to 7-membered cycloalkenyl group may be joined together.
  • group X one or more C atoms may be mono- or polysubstituted by F and / or Cl, preferably F.
  • alkyl groups may be linked together to form a 3 to 7-membered or an alkyl and an alkenyl group to form a 5 to 7-membered cyclic group C atoms one or more times with F and / or CI, preferably F substitution be.
  • a particularly preferred meaning of X is unsubstituted ethylene or propylene or C- M- alkylene, in particular ethylene or propylene, one or two of the same or different substituents independently selected from fluoro, chloro, hydroxy and C ⁇ - 3 alkyl and / or C 2 - 6 -alkenyl or cyclopropyl substituent, wherein two alkyl substituents to form a C 3 - 6 cycloalkyl group or an alkyl and an alkenyl group to form a C 5 . 6 -Cycloalkenyl group can be linked together.
  • the alkylene bridge is monosubstituted or disubstituted by identical or different radicals selected from among methyl, ethyl and isopropyl, it being possible for two alkyl groups to be linked together as indicated to form a cyclic group.
  • X are particularly preferably monosubstituted or disubstituted by identical or different radicals selected from among methyl, ethyl and isopropyl, it being possible for two alkyl groups to be linked together as indicated to form a cyclic group.
  • a particularly preferred meaning of X is unsubstituted -CH 2 -CH 2 -O- or substituted -CH 2 -CH 2 -O- selected from the group consisting of
  • X is -CH 2 -CH 2 -NH- or -CH 2 -CH 2 --NCH 3 - or substituted -CH 2 -CH 2 -NCH 3 - selected from the group consisting of
  • the position of the imino group within the alkylene bridge X is preferably chosen such that together with the amino group NR 1 R 2 or another adjacent amino group no aminal function is formed or two N atoms are not adjacent to one another.
  • the radical R> 10 are -OH, methoxy and hydroxymethyl, in particular -OH.
  • the group X is a -CH 2 -bridge which is unsubstituted or with one or two identical or different C 1-4 -alkyl substituents and / or a substituent selected from C 2 . 6 alkenyl, C 2 . 6- alkynyl, C 3 . 6 -cycloalkyl or C 3 . 6 - Cycloalkyl-C ⁇ - 3- alkyl is substituted, wherein two alkyl substituents may be connected together to form a 3- to 6-membered carbocyclic ring system.
  • X in the meaning -CH 2 - is preferably unsubstituted or monosubstituted or disubstituted with methyl, in that two methyl substituents may be bonded together to form a cyclopropyl group.
  • This third embodiment with respect to X is particularly preferred when Y is a bicyclic group, wherein the. first ring of the bicyclic group is connected to X and the second ring is connected to Z.
  • the bridge W preferably denotes a single bond or ethylene, more preferably a single bond.
  • the bridge Z is preferably a single bond or ethylene which may have one or two methyl substituents which may be linked together to form a cyclopropyl group.
  • Z is particularly preferably a single bond.
  • the group Y preferably has a meaning selected from the group of the bivalent cyclic groups phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, naphthyl, tetrahydronaphthyl, indolyl, dihydroindolyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, isoquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, Benzimidazolyl, benzoxazolyl, chromanyl, chromene-4-onyl, benzothienyl, or benzofuranyl, more preferably phenyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl, wherein the aforementioned cyclic groups one or more times to one or more carbon atom
  • the bridges X and Z are preferably connected in para-position to the group Y.
  • Y has one of the following meanings
  • Y has one of the following meanings
  • cyclic groups may be monosubstituted or polysubstituted by one or more C atoms with identical or different radicals R 20 , in the case of a phenyl ring additionally also simply with nitro, and / or one or more NH groups with R 21 be substituted. If the group Y is selected from the group of bivalent bicyclic groups
  • bicyclic groups may be monosubstituted or polysubstituted by one or more C atoms with the same or different radicals R 20 , in the case of a phenyl ring additionally also simply with nitro, and / or one or more NH groups with R 21 can be substituted
  • the bridge X is preferably a -CH 2 group which may be substituted for X according to the third embodiment described above.
  • the group Y is preferably unsubstituted or monosubstituted or disubstituted.
  • substituents R 20 of the group Y are selected from the group consisting of fluorine, chlorine, bromine, cyano, nitro, d-4 alkyl, C 2nd 6 alkenyl, hydroxy, ⁇ -hydroxy-3 C ⁇ _ alkyl, C
  • R 20 of the group Y are selected from the group consisting of fluorine, chlorine, bromine, cyano, C 1-3 -alkyl, C 1-3 -alkoxy, d- 4 -
  • the group Y is substituted phenylene of ⁇ 1
  • group A is selected from the group of bivalent cyclic ones
  • A is one of the groups listed below
  • substituents R 20 of group A are independently fluorine, chlorine, bromine, CF 3 , amino, methoxy and C ⁇ alkyl.
  • the groups A are unsubstituted or monosubstituted with R 20 as indicated.
  • Preferred meanings of group B according to a first preferred embodiment are selected from the group consisting of phenyl, pyridyl, thienyl and furanyl.
  • the group B is phenyl.
  • the group B in the meanings indicated may be monosubstituted or polysubstituted by identical or different radicals R 20 , and additionally a phenyl group may also be monosubstituted by nitro.
  • the group is B is unsubstituted or monosubstituted, disubstituted or trisubstituted, in particular unsubstituted or monosubstituted or disubstituted.
  • the substituent is preferably in the para position to the group A.
  • Preferred substituents R 20 of group B are selected from among fluorine, chlorine, bromine, cyano, nitro, C 1-4 -alkyl, hydroxy, CHF 2 , CHF 2 -O-, hydroxy-C 1-3 -alkyl, 4 alkoxy, trifluoromethyl, trifluoromethoxy, C ⁇ alkynyl, carboxy, C ⁇ - 4 alkoxycarbonyl, ⁇ - (C 1. 4 alkoxy) -d- 3- alkyl, C 1 - alkoxy-carbonylamino, amino -, d- 4 -alkyl-amino, di- (C 1 - 4 -alkyl) - amino, cyclo-C 3 . 6 -alkylenimino, aminocarbonyl, d-alkyl-amino-carb ⁇ nyl- and di- (C 1 - 4 - alkyl) -aminocarbonyl-.
  • Substituents R 20, particularly preferred the group B are selected from the group consisting of fluorine, chlorine, bromine, cyano, CF 3, C- ⁇ - 3 alkyl, C ⁇ - 4 alkoxy and trifluoromethoxy.
  • Very particularly preferred substituents R 20 of group B are selected from the group consisting of chlorine, bromine and methoxy.
  • the meaning of the group B is preferably selected from d- 6 alkyl, C 2nd 6 -alkenyl, C 2 - 6 alkynyl, C 3-7 cycloalkyl, C. 5 7- Cycloalkenyl, C 3 . 7 - cycloalkyl-d- alkyl 3 -aIkyl-, C3 7 cycloalkenyl-d-3, C 3 - 7 cycloalkyl-alkenyl C ⁇ - 3, C. 3 7 - cycloalkyl-d- 3- alkynyl, wherein one or more carbon atoms in the groups mentioned above for B may be monosubstituted or polysubstituted by fluorine.
  • one or more C atoms may be substituted with the same or different R 20 .
  • Particularly preferred according to this embodiment are the groups C 3 . 6- alkyl, C 3 . 6 - alkenyl, C 3 . 6- alkynyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl ,.
  • B according to this second embodiment is cyclohexenyl which is unsubstituted or has 1, 2 or 3 identical or different substituents R 20 , in particular methyl.
  • R 4 is preferably H, C ⁇ alkyl, C 3 - 6 cycloalkyl, and C. 3 6 -cycloalkyl-methyl, in particular H, methyl, ethyl, propyl, i-propyl, n-propyl, Cylcopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopentylmethyl, cyclohexymethyl.
  • R 4 is H or methyl.
  • the substituent R 13 preferably has one of the meanings given for R 16 .
  • R 13 is H, d-4 alkyl, C 3rd 7 -cycloalkyl, d- T- cycloalkyl-ds-alkyl, ⁇ -hydroxy-C 2 . 3 -alkyl-, ⁇ - (C ⁇ - alkoxy) -C 2 - 3 -alkyl-.
  • R 13 is H or C 1 -alkyl.
  • the abovementioned alkyl groups may be monosubstituted by CI or monosubstituted or polysubstituted by F.
  • R 15 are H, C 1-4 alkyl, C 3 . 7 cycloalkyl, C 3 - 7 - cycloalkyl-d- 3 alkyl, wherein, as hereinbefore defined, in each case one or more C atoms may additionally be mono- or polysubstituted with one F and / or in each case or two C atoms independently of one another additionally may simply be substituted with CI or Br. More preferably R 15 is H, CF 3 , methyl, ethyl, propyl or butyl.
  • the substituent R 16 is preferably H, d- 4- alkyl, C 3 . 7 -cycloalkyl, C 3 - 7 -cycloalkyl-C 3 -alkyl, ⁇ -hydroxy-C 2 . 3 alkyl or ⁇ - (C 1-4 alkoxy) C. 2 3 -alkyl-, where, as defined above, in each case one or more C atoms additionally mono- or polysubstituted with F and / or in each case one or two C atoms can be additionally substituted independently with CI or Br independently.
  • R 16 is H, CF 3 , d. 3- alkyl, C 3 . 6 -cycloalkyl or C 3 . 6 - Cycioalkyl-d- 3- alkyl-.
  • R 17 for one of the R 16 is given as preferred meanings or • phenyl, phenyl-3 C ⁇ - alkyl, pyridinyl or C ⁇ - 4 -alkylcarbonyl.
  • R 17 particularly preferably has one of the meanings given for R 16 as being preferred.
  • a means or both are of the substituents R 18 and R 19 are independently hydrogen or C 4 alkyl, especially hydrogen.
  • the substituent R 20 is preferably halogen, hydroxy, cyano, C ⁇ - 4 alkyl, C 2 - 4 alkenyl, C 2 . Alkynyl, C 3-7 cycloalkyl, C.
  • Particularly preferred meanings of the group R 20 are halogen, hydroxy, cyano, d- 4 - alkyl, C 3 - 7 cycloalkyl, d-3 alkylcarbonyl and d-4 alkoxy, wherein, as hereinbefore defined, in each case one or more C Atoms may additionally be mono- or polysubstituted with F and / or in each case one or two C atoms independently of one another may additionally be substituted simply by Cl or Br.
  • R 20 denotes F, CI, Br, I, OH, cyano, methyl, difluoromethyl, trifluoromethyl, ethyl, n-propyl, acetyl, isopropyl, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, n-propoxy or isobutyl. propoxy.
  • the substituent R 22 is preferably d- 4 alkoxy, C ⁇ alkylthio, carboxy, C ⁇ - 4 alkylcarbonyl, d- alkoxycarbonyl, aminocarbonyl, d- 4 alkylaminocarbonyl, di- (d- C4 alkyl) aminocarbonyl, C 1 -C 4 alkylsulfonyl, C 1 -C 4 alkylsulfinyl, C 1 -C 4 alkylsulfonylamino, amino, C 1 -C 4 -alkylamino, di (C 1-4 -alkyl) amino, C 1-4 -alkyl carbonyl-amino, hydroxy-d- 3 - alkylaminocarbonyl, aminocarbonylamino or d ⁇ -alkylaminocarbonyl-amino-, where, as defined above, in each case one or more carbon atoms additionally one or more times with F and / or in each case one or
  • R 22 are C ⁇ - 4 - alkoxy, d- 3 alkylcarbonyl, amino, d ⁇ alkylamino, di (C 1 - 4 alkyl) amino, .worin one or more H Atoms may be replaced by fluorine.
  • R 21 are d-- . alkyl, C 1-4 -alkylsulfonyl, -SO 2 -NH 2 , -SO 2 -NH-C ⁇ - 3 -alkyl, -SO 2 -N (C 1 - 3 -alkyl) 2 and cyclo-C 3 . 6 -alkyleniminosulphonyl-, where, as defined above, in each case one or more C atoms additionally mono- or polysubstituted with F and / or in each case one or two C atoms, independently of one another, can additionally be substituted simply by Cl or Br. Most particularly preferably R 21 d- 4 alkyl or CF 3.
  • Cy is preferably a C 3 . 7 -cycloalkyl, in particular a C 3 . 6- cycloalkyl group, a C 5 . 7- cycloalkenyl group, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,
  • Very particularly preferred meanings of the group Cy are C 3 . 6 -cycioalkyl, pyrrolidinyl and piperidinyl, which may be substituted as indicated.
  • aryl is preferably phenyl or naphthyl, in particular phenyl.
  • heteroaryl preferably includes pyridyl, indolyl, quinolinyl and benzoxazolyl.
  • Particularly preferred compounds according to the invention can have a general formula Ha, IIb, IIc, IId, IIe, IIf, Hg, IIh, in particular IIa, IIb, He and IIf,
  • R 1 , R 2 , X and Z have one of the aforementioned preferred meanings and
  • L 3 independently of one another have one of the meanings given for R 20 .
  • n, p independently of one another denote the values 0, 1 or 2, p also the value 3.
  • m, n, p independently of one another denote the values 0, 1 or 2, p also the value 3.
  • L 1 is fluorine, chlorine, bromine, cyano, d-3 alkyl, d-3 alkoxy, C ⁇ alkoxycarbonyl, trifluoromethyl, trifluoromethoxy, nitro,
  • n 0 or 1
  • L 2 is fluorine, chlorine, bromine, CN, amino, CF 3, methoxy and d- 3 alkyl,
  • L 3 independently of one another selected from the meanings fluorine, chlorine, bromine, cyano, nitro, d- C4 alkyl, hydroxy, ⁇ -hydroxy-d- 3 alkyl, C ⁇ alkoxy, trifluoromethyl, trifluoromethoxy, C 2 - 4 - alkynyl, carboxy, C ⁇ alkoxycarbonyl, ⁇ - (d- alkoxy) C 1 - 3 alkyl, C 1 - 4 alkoxy-carbonylamino, amino, d ⁇ -alkyl-amino, di- (C ⁇ -alky -amino, cyclo-C 3 - 6 -alkylenimino-, aminocarbonyl, C ⁇ alkyl-amino-carbonyl or di- (C 1 - alkyl) -amino-carbonyl, particularly preferably fluorine , chlorine, bromine, cyano, CF 3, d- C3 alkyl, d-4
  • p 0, 1, 2 or 3, in particular 1 or 2.
  • R 1 prop-2-enyl, but-2-enyl, prop-2-ynyl, but-2-ynyl, (1-hydroxy-C 3 6 cycloalkyl.) - methyl, tetrahydropyran-3-yl, tetrahydropyran-4 -yl, 2,3-dihydroxy-C 3 . 5 -alkyl, and
  • R 2 is H, d-4 alkyl, C 3rd 5 alkenyl, C 3 . 5- alkynyl, C 3 . 7 cycloalkyl, C 3 - 7 cycloalkyl-C
  • R 1 , R 2 are joined together and together with the N-atom to which they are attached form a heterocyclic group selected from 3,4-dihydroxypyrrolidinyl, 3,4-dihydroxypiperidinyl, 3,5-dihydroxypiperidinyl, ( Hydroxymethyl) -hydroxy-pyrrolidinyl, (hydroxymethyl) -hydroxy-piperidinyl, (1-hydroxyethyl) -hydroxy-pyrrolidinyl, (1-hydroxyethyl) -hydroxy-piperidinyl, (1-hydroxy-1-methylethyl) -hydroxy-pyrrolidinyl, ( 1-hydroxy-1-methylethyl) -hydroxy-piperidinyl, (1-hydroxycyclopropyl) -hydroxy-pyrrolidinyl, (1-hydroxycyclopropyl) -hydroxy-piperidinyl, (1-hydroxy-cyclopropyl) -hydroxy-piperidinyl, (1-hydroxy-cyclopropyl) -pyrrolidiny ⁇ ,
  • X is ethylene or propylene or unsubstituted one or two identical or different substituents independently selected from fluoro, chloro, hydroxy and C ⁇ - 3 alkyl and / or C 2 - 6 -alkenyl or cyclopropyl substituent, wherein two Alkyl substituents to form a C 3 .
  • e-cycloalkyl group, or an alkyl and an alkenyl group to form a C 5 - 6 cycloalkenyl group may be connected to each other, or
  • -CH 2 -CH CH-, -CH 2 -C ⁇ C-, -CH 2 -CH 2 -O- or -CH 2 -CH 2 -NR 4 -, which are unsubstituted or one or two identical or different substituents independently selected from fluorine and d-3 alkyl and / or a cyclopropyl-substituents, while two alkyl groups to form a C 3 - 6 cycloalkyl group, or if an alkyl group is the radical R 4, 'under Formation of a pyrrolidine or piperidine group may be linked together.
  • halogen denotes an atom selected from the group consisting of F, Cl, Br and I, in particular F, Cl and Br.
  • d- n- alkyl wherein n has a value of 3 to 8, means a saturated, branched or unbranched hydrocarbon group having 1 to n carbon atoms.
  • examples of such groups include methyl, ethyl, n-propyl, iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl, tert-pentyl, nH 'exyl, iso-hexyl, etc.
  • C ⁇ _ n -alkylene where n may have a value of 1 to 8, means a saturated, branched or unbranched hydrocarbon bridge having 1 to n carbon atoms.
  • groups include methylene (-CH 2 -), ethylene (-CH 2 -CH 2 -), 1-methyl-ethylene (-CH (CH 3 ) -CH 2 -), 1, 1-dimethyl-ethylene (- C (CH 3 ) 2 -CH 2 -), n -prop-1, 3-ylene (-CH 2 -CH 2 -CH 2 -), 1-methylprop-1, 3-ylene (-CH (CH 3 ) -CH 2 -CH 2 -), 2-methylprop-1,3-ylene (-CH 2 -CH (CH 3 ) -CH 2 -), etc., as well as the corresponding mirror-image forms.
  • Double bond Examples of such groups include vinyl, 1-propenyl, 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, etc.
  • groups include ethynyl, 1-propynyl, 2-propynyl, isopropynyl, 1-butynyl, 2-butynyl, 3-butynyl, 2-methyl-1-propynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 3-methyl-2-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, etc.
  • d- n- alkoxy denotes a C n- alkyl-O-group, in which d- n- alkyl is as defined above.
  • examples of such groups include methoxy, ethoxy, n-propoxy, iso -propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, iso-pentoxy, neo-pentoxy, tert-pentoxy, n- Hexoxy, iso-hexoxy etc.
  • d- n- alkylthio denotes a d- n- alkyl-S-group in which d- n- alkyl is as defined above.
  • Examples of such groups include methylthio, ethylthio, n-propylthio, iso-propylthio, n-butylthio, iso-butylthio, sec-butylthio, tert-butylthio, n-pentylthio, isopentylthio, neo-pentylthio, tert-pentylthio, n-butylthio Hexylthio, iso-hexylthio, etc.
  • groups include methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, iso -propylcarbonyl, n-butylcarbonyl, iso-butylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl, n-pentylcarbonyl, iso-pentylcarbonyl, neo-pentylcarbonyl, tert-pentylcarbonyl, n-butyl Hexylcarbonyl, iso-hexylcarbonyl, etc.
  • n- Cycloalkyl denotes a saturated mono-, bi-, tri- or spirocarbocyclic, preferably monocarbocyclic group having 3 to n C atoms.
  • groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclododecyl, bicyclo [3.2.1.] Octyl, spiro [4.5] decyl, norpinyl, norbornyl, norcaryl, adamantyl, etc.
  • C 5 - n -cycloalkenyl denotes a monounsaturated mono-, bi-, tri- or spirocarbocyclic, preferably monocarbocyclic group having 5 to n C atoms.
  • examples of such groups include cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, etc.
  • aryl refers to a carbocyclic aromatic ring system such as phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, indenyl, pentalenyl, azulenyl, biphenylenyl, etc.
  • a particularly preferred meaning of "aryl” is phenyl.
  • cyclo-C 3 . 6 -alkyleneimino- refers to a 4- to 7-membered ring having from 3 to 6 methylene units and an imino group, the bond to the rest of the molecule being via the imino group.
  • cyclo-C 3 . 6- Alkylenimino-carbonyl denotes a previously defined cyclo-C 3 _ 6 - alkylenimino ring which is connected via the imino group with a carbonyl group.
  • heteroaryl used in this application denotes a heterocyclic, aromatic ring system which, in addition to at least one C atom, comprises one or more heteroatoms selected from N, O and / or S.
  • Examples of such groups are furanyl, thiophenyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, 1, 2,3-triazolyl, 1,3,5-triazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1, 2, 3-triazinyl, 1, 2,4-triazinyl, 1, 3,5-triazinyl, 1, 2,3-oxadiazolyl, 1, 2,4-oxadiazolyl, 1, 2,5-oxadiazolyl, 1, 3,4- Oxadiazolyl, 1, 2,3-thiadiazolyl, 1, 2,4-thiadiazolyl, 1, 2,5-thiadiazolyl, 1, 3,4-thiadiazolyl, tetrazolyl, thiadiazinyl, indolyl, isoindolyl, benzofuranyl,
  • heteroaryl also includes the partially hydrogenated heterocyclic, aromatic Ring systems, " in particular of the ring systems listed above Examples of such partially hydrogenated heterocycles are 2,3-di hydrobenzofuranyl, pyrolinyl, pyrazolinyl, indolinyl, oxazolidinyl, oxazolinyl, oxazepinyl, etc.
  • Particularly preferred heteroaryl means a heteroaromatic mono- or bicyclic ring system.
  • Ci- n alkyl as defined above, with a C 3 . 7 -cycloalkyl, aryl or heteroaryl group is substituted.
  • unsaturated for example in “unsaturated carbocyclic group” or “unsaturated heterocyclic group”, as used in particular in the definition of the group Cy, in addition to the mono- or polyunsaturated groups also includes the corresponding fully unsaturated groups, but especially mono- and diunsaturated groups.
  • the H atom of an existing carboxy group or an H atom bound to an N atom (imino or amino group) can each be replaced by a residue which can be split off in vivo.
  • a N-atom in vivo radical is understood to mean, for example, a hydroxy group, an acyl group such as the benzoyl or pyridinoyl group or a C 16 alkanoyl group such as formyl, acetyl, propionyl, butanoyl, pentanoyl or Hexanoyl group, an allyloxycarbonyl group, a d- 16- alkoxycarbonyl group such as the methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentoxycarbonyl, hexyloxycarbonyl, octyloxycarbonyl, nonyloxycarbon
  • alkoxycarbonyl group such as the benzyloxycarbonyl, phenylethoxycarbonyl or Phenylpropoxycarbonyl distr, a C ⁇ - 3 alkylsulfonyl-C. 2 4 -alkoxycarbonyl, C 1 - 3 alkoxy-C 2 - 4 alkoxy-C 2 - 4 alkoxycarbonyl, or R e CO-O- (R f CR g) -O-CO-group in which
  • R e is a C 8 -alkyl, C 5 . 7 -cycloalkyl, phenyl or phenyl-C 1-3 -alkyl group,
  • R f is a hydrogen atom, a d. 3 alkyl, C 5-7 cycloalkyl or phenyl group and R g represents a hydrogen atom, a C 3 alkyl or R 8 CO-O- (R f CR g) -O- group wherein R e to , R g are as defined above, in addition, for an amino group, the phthalimido group is contemplated, wherein the above-mentioned ester groups can also be used as in vivo into a carboxy group convertible group.
  • radicals and substituents described above may be mono- or polysubstituted by fluorine in the manner described.
  • Preferred fluorinated alkyl radicals are fluoromethyl, difluoromethyl and trifluoromethyl.
  • Preferred fluorinated alkoxy radicals are fluoromethoxy, difluoromethoxy and trifluoromethoxy.
  • Preferred fluorinated alkylsulfinyl and alkylsulfonyl groups are trifluoromethylsulfinyl and trifluoromethylsulfonyl.
  • the compounds of the general formula I according to the invention may have acid groups, mainly carboxyl groups, and / or basic groups, e.g. Amino functions.
  • Compounds of general formula I can therefore be used as internal salts, as salts with pharmaceutically acceptable inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, sulfonic acid or organic acids (such as maleic acid, fumaric acid, citric acid, tartaric acid or acetic acid) or as salts with pharmaceutically acceptable bases such as Alkali or alkaline earth metal hydroxides or carbonates, zinc or ammonium hydroxides or organic amines such as Diethylamine, triethylamine, triethanolamine, and the like. available.
  • pharmaceutically acceptable inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, sulfonic acid or organic acids (such as maleic acid, fumaric acid, citric acid, tartaric acid or acetic acid)
  • pharmaceutically acceptable bases such
  • the compounds according to the invention can be obtained using synthesis methods known in principle.
  • the compounds are preferably obtained according to the preparation process according to the invention explained in more detail below.
  • the halogen compound A.1 is reacted with the alkyne compound A.2 in a molar ratio of about 1.5: 1 to 1: 1.5 under a protective gas atmosphere in the presence of a suitable palladium catalyst, a suitable base and copper (I). iodide reacted in a suitable solvent.
  • a preferred amount of copper (I) iodide in this case is in the range from 1 to 15 mol%, in particular from 5 to 10 mol%, based on the educt A.1.
  • Suitable palladium catalysts are, for example, Pd (PPh 3 ), Pd 2 (dba) 3 , Pd (OAc) 2 , Pd (PPh 3 ) 2 Cl 2 , Pd (CH 3 CN) 2 Cl 2 , Pd (dppf) Cl 2 ,
  • the palladium catalyst is preferably used in an amount of 1 to 15 mol%, in particular 5 to 10 mol%, based on the educt A.1.
  • Suitable bases are in particular amines, such as triethylamine or
  • Ethyldiisopropylamine as well as Cs 2 CO 3 .
  • the base is preferably used at least in equimolar amount based on the educt A.1, in excess or as a solvent.
  • suitable solvents are dimethylformamide or ethers, such as tetrahydrofuran, including mixtures thereof.
  • the reaction is carried out in a period of about 2 to 24 hours in a temperature range of about 20 to 90 ° C.
  • the resulting alkyne compound A.3 is reacted directly or after prior purification with methanesulfonyl chloride to methanesulfonate derivative A.4.
  • the reaction conditions to be observed are known to those skilled in the art.
  • Advantageous solvents are halogenated hydrocarbons, such as dichloromethane. Suitable reaction temperatures are usually in a range of 0 to 30 ° C.
  • reaction solution containing the methanesulfonate derivative A.4 or the purified methanesulfonate derivative A.4 dissolved in a suitable solvent is reacted with an amine H-NR R 2 to give the final product A.5 and then optionally purified.
  • the amine H-NR 1 R 2 has a further primary or secondary amine function, then this is advantageously provided beforehand with a protective group which can be cleaved off again after the reaction has ended using methods known from the literature.
  • the product thus obtained can be converted into the salt form, for example, by reaction with a corresponding acid.
  • a preferred molar ratio of the derivative A.4 to the amine compound is in the range of 1, 5: 1 to 1: 1.5.
  • Suitable solvents are dimethylformamide or ethers such as tetrahydrofuran, including mixtures thereof.
  • the reaction to the product A.5 is advantageously carried out in a temperature range of about 20 to 90 ° C.
  • the halogen compound B.2 is reacted with the alkyne compound B.1 in a molar ratio of about 1.5: 1 to 1: 1.5 under a protective gas atmosphere in the presence of a suitable palladium catalyst, a suitable base and copper (I). iodide reacted in a suitable solvent.
  • a suitable palladium catalyst e.g., palladium
  • a suitable base e.g., palladium
  • copper (I) iodide
  • the resulting alkyne compound B.3 is reacted directly or after prior purification with methanesulfonyl chloride to methanesulfonate derivative B.4.
  • the reaction conditions to be observed in this case are again to be taken from the statements made in Scheme A.
  • the reaction solution containing the methanesulfonate derivative B.4 or the purified methanesulfonate derivative B.4 dissolved in a suitable solvent is reacted with an amine H-NR 1 R 2 to give the final product B.5 and then optionally purified. Again, the comments on Scheme A apply.
  • the halogen compound C.1 is reacted with the alkyne compound C.2 in a molar ratio of about 1.5: 1 to 1: 1.5 under a protective gas atmosphere in the presence of a suitable palladium catalyst, a suitable base and copper ( l) iodide reacted in a suitable solvent directly to the product C.3.
  • Reaction Scheme D An alternative synthesis is shown in Reaction Scheme D.
  • a suitable palladium catalyst e.2
  • a suitable base e.g., copper (I) iodide
  • Halogen compound A.1, B.2, C.1 and D.2 are reacted with sodium iodide in the presence of ⁇ /, ⁇ / '- dimethylethylenediamine and copper (I) iodide in a suitable solvent to the corresponding iodine compound.
  • An advantageous molar ratio of the halogen compound to sodium iodide is 1: 1, 8 to 1: 2.3.
  • ⁇ /, ⁇ / '- Dimethyl-ethylenediamine is advantageously in a molar ratio of 10 to 30 mol% based on the
  • Halogen compound A.1, B.2, C.1 or D.2 used.
  • Preferred amounts of copper (I) iodide are in the range of 5 to 20 mol% based on the halogen compound A.1, B.2, C.1 or D.2.
  • a hiebei suitable solvent is, for example, 1, 4-dioxane.
  • Suitable reaction temperatures are in the range of about 20 to 110 ° C. The reaction is essentially complete after 2 to 72 hours.
  • stereoisomeric compounds of the formula (I) can be separated by customary methods.
  • the separation of the respective diastereomers is possible due to their different physicochemical properties, e.g. by fractional crystallization from suitable solvents, by high pressure liquid or column chromatography using chiral or preferably achiral stationary phases.
  • racemates covered by the general formula (I) succeeds, for example, by HPLC on suitable chiral stationary phases (eg Chiral AGP, Chiralpak AD). Racemates which contain a basic or acidic function can also be resolved via the diastereomeric, optically active salts which, when reacted with an optically active acid, for example (+) - or (-) - tartaric acid, (+) - or (-) ) -Diacetyltartaric acid, (+) - or (-) - monomethyl tartrate or (+) - camphorsulfonic acid, or an optically active base, for example with (f?) - (+) - 1-phenylethylamine, (S) - (-) 1-phenylethylamine or (S) -brucine.
  • an optically active acid for example (+) - or (-) - tartaric acid, (+) - or (-) ) -Diacetyltartaric acid, (+) - or (-) - mono
  • the racemate of a compound of the general formula (I) is reacted with one of the above-mentioned optically active acids or bases in an equimolar amount in a solvent and the resulting crystalline, diastereomeric, optically active salts taking advantage of their different solubility separated.
  • This reaction can be carried out in any kind of solvents as long as they make a sufficient difference in the solubility of the salts respectively.
  • methanol, ethanol or mixtures thereof, for example in the volume ratio 50:50, are used.
  • each of the optically active salts is dissolved in water, carefully neutralized with a base such as sodium carbonate or potassium carbonate, or with a suitable acid, for example, with dilute hydrochloric acid or aqueous methanesulfonic acid, thereby giving the corresponding free compound in the (+) - or ( -) - Form received.
  • a base such as sodium carbonate or potassium carbonate
  • a suitable acid for example, with dilute hydrochloric acid or aqueous methanesulfonic acid
  • the compounds of the formula (I) can be converted into their salts, in particular for the pharmaceutical application, into their physiologically and pharmacologically tolerable salts. These salts may be present on the one hand as physiologically and pharmacologically acceptable acid addition salts of the compounds of the formula (I) with inorganic or organic acids. On the other hand, in the case of acidically bound hydrogen by reaction with inorganic bases, the compound of formula (I) can also be converted into physiologically and pharmacologically acceptable salts with alkali metal or alkaline earth metal cations as the counterion.
  • Hydrochloric acid hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid are suitable for the preparation of the acid addition salts. Furthermore, mixtures of the abovementioned acids can be used. To illustrate the alkali and alkaline earth metal salts of
  • Compounds of formula (I) with acidic hydrogen are preferably the alkali and alkaline earth hydroxides and hydrides into consideration, the hydroxides and hydrides of the alkali metals, in particular of sodium and potassium are preferred, sodium and potassium hydroxide are particularly preferred.
  • the compounds of the present invention have activity as antagonists of the MCH receptor, particularly the MCH-1 receptor, and show good affinities in MCH receptor binding studies. Pharmacological test systems for MCH antagonistic properties are described in the experimental section below.
  • the compounds of the invention are advantageously useful as pharmaceutical agents for the prophylaxis and / or treatment of phenomena and / or diseases caused by MCH or in another causal relationship with MCH.
  • the compounds according to the invention have a low toxicity, a good oral absorbability and intracerebral transitivity, in particular brain clearance.
  • MCH antagonists which have at least one compound of the invention, especially in mammals, such as rats, mice, guinea pigs, rabbits, dogs, cats, sheep, horses, pigs, cattle, monkeys and humans, for the treatment and / or prophylaxis of Phenomena and / or diseases caused by MCH or in another causal relationship with MCH.
  • Diseases caused by MCH or in another causal relationship with MCH are, in particular, metabolic disorders such as obesity and eating disorders such as bulimia including bulimia nervosa.
  • the indications of obesity include especially exogenous obesity, hyperinsulinar obesity, hyperplasmic obesity, hyperphyseal obesity, hypoplasmic obesity, hypothyroid obesity, hypothalamic obesity, symptomatic obesity, infantile obesity, upper body obesity, alimentary obesity, hypogonadal obesity, central obesity.
  • cachexia, anorexia and hyperphagia are to be mentioned in this indication environment.
  • compounds of the invention may be useful in reducing hunger, curbing appetite, controlling eating behavior, and / or inducing satiety.
  • diseases caused by MCH or otherwise causally related to MCH may also include hyperlipidemia, cellulitis,
  • Compounds of the invention are also useful as agents for the prophylaxis and / or treatment of other diseases and / or disorders, especially those associated with obesity, such as diabetes, diabetes mellitus, especially type II diabetes, hyperglycemia, especially chronic hyperglycemia, diabetic complications, including diabetic Retinopathy, diabetic neuropathy, diabetic nephropathy, etc., insulin resistance, pathological glucose tolerance, encephalorrhagia, cardiac insufficiency, cardiovascular diseases, especially arteriosclerosis and hypertension, arthritis and gonitis.
  • other diseases and / or disorders especially those associated with obesity, such as diabetes, diabetes mellitus, especially type II diabetes, hyperglycemia, especially chronic hyperglycemia, diabetic complications, including diabetic Retinopathy, diabetic neuropathy, diabetic nephropathy, etc., insulin resistance, pathological glucose tolerance, encephalorrhagia, cardiac insufficiency, cardiovascular diseases, especially arteriosclerosis and hypertension, arthritis and gonitis.
  • MCH antagonists and formulations according to the invention can advantageously be used in combination with an alimentary therapy, such as, for example, an alimentary diabetes therapy, and exercise.
  • Another area of indication for which the compounds of the invention are advantageously useful is the prophylaxis and / or treatment of voiding disorders such as urinary incontinence, overactive bladder, urinary urgency, nocturia, enuresis, with overactive bladder and urinary urgency with or without benign prostatic hyperplasia Need to be connected.
  • voiding disorders such as urinary incontinence, overactive bladder, urinary urgency, nocturia, enuresis, with overactive bladder and urinary urgency with or without benign prostatic hyperplasia Need to be connected.
  • the compounds of the invention are potentially useful to prevent and / or treat dependencies such as alcohol and / or nicotine addiction and / or withdrawal symptoms, such as weight gain in nicotine withdrawal from smokers.
  • dependencies is here generally an irresistible urge to take an addictive substance and / or perform certain acts, in particular either to achieve a feeling of well-being or to eliminate discomfort understood.
  • an addictive dependency is understood here as “dependency”.
  • “Withdrawal symptoms” are generally understood here to be symptoms that occur or may occur in the withdrawal of addictive substances in patients dependent on one or more such addictive substances.
  • the compounds of the present invention are potentially useful as agents to reduce or stop the consumption of tobacco, to treat or prevent nicotine dependence and / or to treat or prevent nicotine withdrawal symptoms, reduce cravings for tobacco and / or nicotine and generally Remedy for smoking.
  • the compounds of the present invention may be useful to prevent or at least reduce the weight gain associated with nicotine withdrawal from smokers.
  • the substances may furthermore be suitable as active ingredients which prevent or at least reduce the desire for and / or a relapse into dependence on addictive substances.
  • Addictive substances are understood to mean in particular but not exclusively psycho-motor active substances, such as narcotics or intoxicants, in particular alcohol, nicotine, cocaine, amphetamine, opiates, benzodiazepines and barbiturates.
  • the dosage required to achieve a corresponding effect is expediently from 0.001 to 30 mg / kg body weight, preferably from 0.01 to 5 mg / kg body weight, by intravenous or subcutaneous administration, and from 0.01 to 50 mg / kg by oral, nasal or inhalative administration Body weight, preferably 0.1 to 30 mg / kg body weight, once to three times daily.
  • the compounds of general formula I according to the invention optionally in combination with other active substances, as described in more detail below, together with one or more inert conventional carriers and / or diluents, e.g. with cornstarch, lactose, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerin, water / sorbitol, water / polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or their suitable mixtures , into common pharmaceutical preparations such as tablets, dragees, capsules, wafers, powders, granules, solutions, emulsions, syrups, inhalation aerosols, ointments, suppositories.
  • inert conventional carriers and / or diluents e.g. with cornstarch, lactos
  • compositions comprising at least one alkyne compound according to the invention and / or a salt according to the invention in addition to optionally one or more physiologically acceptable excipients.
  • Such compositions may, for example, also be foodstuffs which may be solid or liquid, in which the compound according to the invention is incorporated.
  • suitable further active substances are, in particular, those which, for example, enhance the therapeutic effectiveness of an MCH antagonist according to the invention with regard to one of the indicated indications and / or which allow a reduction in the dosage of an MCH antagonist according to the invention.
  • one or more further active substances are selected from the group consisting of active ingredients for the treatment of diabetes, - agents for the treatment of diabetic complications,
  • agents for the treatment of hypertension agents for the treatment of hyperlipidemia, including arteriosclerosis, - agents for the treatment of dyslipidemia, including arteriosclerosis, agents for the treatment of arthritis,
  • Examples of drugs for the treatment of diabetes are insulin sensitizers, insulin secretagogues, biguanides, insulins, ⁇ -glucosidase inhibitors, ⁇ 3 adreno receptor agonists.
  • Insulin sensitizers include glitazones, especially pioglitazones and its salts (preferably hydrochlorides), troglitazones, rosiglitazones and its salts (preferably maleates), JTT-501, GI-262570, MCC-555, YM-440, DRF-2593, BM-13 1258, KRP-297, R-119702, GW-1929.
  • glitazones especially pioglitazones and its salts (preferably hydrochlorides), troglitazones, rosiglitazones and its salts (preferably maleates), JTT-501, GI-262570, MCC-555, YM-440, DRF-2593, BM-13 1258, KRP-297, R-119702, GW-1929.
  • Insulin secretion enhancers include sulfonylureas such as tolbutamide, chlorpropamide, tolzamide, acetohexamide, glyclopyramide and its ammonium salts, glibenclamide, gliclazide, glimepiride. Further examples of insulin secretion accelerators are repaglinide, nateglinide, mitiglinide (KAD-1229), JTT-608.
  • Biguanides include metformin, buformin, phenformin.
  • Insulins include insulins derived from animals, particularly cattle or swine, semi-synthetic human insulins enzymatically synthesized from animal-derived insulin, human insulin obtained by genetic engineering, for example from Escherichia coli or yeasts. Further, insulin is understood to be insulin zinc (containing 0.45 to 0.9 weight percent zinc) and protamine-insulin zinc available from zinc chloride, protamine sulfate and insulin. In addition, insulin can be obtained from insulin fragments or derivatives (e.g., INS-1, etc.).
  • Insulin may also include different types, for example, with regard to the time of onset and duration of action ("ultra-immediate action type”, “immediate action type”, “two-phase type”, “intermediate type”, “extended action type”, etc.), which are selected depending on the pathological condition of the patients.
  • ⁇ -glucosidase inhibitors include acarbose, voglibose, miglitol, emiglitate.
  • ⁇ 3 adreno receptor agonists include AJ-9677, BMS-196085, SB-226552, AZ40140.
  • drugs for the treatment of diabetes include ergoset, pramiintide, leptin, BAY-27-9955 and glycogen phosphorylase inhibitors, sorbitol dehydrogenase inhibitors, protein tyrosine phosphatase 1 B inhibitors, dipeptidyl protease inhibitors, glipizide, glyburide.
  • Agents for the treatment of diabetic complications include, for example, aldose reductase inhibitors, glycation inhibitors, protein kinase C inhibitors, DPPIV blockers, GLP-1 or GLP-1 analogs, SGLT-2 inhibitors.
  • Aldose reductase inhibitors are, for example, Tolrestat, Epalrestat, Imirestat, Zenarestat, SNK-860, Zopolrestat, ARI-50 ⁇ , AS-3201.
  • An example of a glycation inhibitor is pimagedine.
  • Protein kinase C inhibitors are, for example, NGF, LY-333531.
  • DPPIV blockers are for example LAF237 (Novartis), MK431 (Merck) as well as 815541, 823093 and 825964 (all GlaxoSmithkline).
  • GLP-1 analogs are for example Liraglutide (NN2211) (NovoNordisk), CJC1131 (Conjuchem), Exenatide (Amlyin).
  • SGLT-2 inhibitors are AVE-2268 (Aventis) and T-1095 (Tanabe, Johnson & Johnson). Alprostadil, thiapride hydrochloride, cilostazol, mexiletine hydrochloride, ethyl eicosapentate, memantine, pimagedine (ALT-711), other than the aforementioned drugs for the treatment of diabetic complications.
  • Agents for the treatment of obesity include lipase inhibitors and anorectics.
  • a preferred example of a lipase inhibitor is orlistat.
  • preferred anorectic agents are phentermine, mazindol, dexfenfluramine, fluoxetine, sibutramine, baiamine, (S) -sibutramine, SR-141716, NGD-95-1.
  • anorectics are also counted for the purposes of this application to the drug group of anti-obesity drugs, the ß 3 agonists, thyromimetic agents and NPY antagonists are highlighted.
  • the scope of the substances which may be considered as preferred antiobesity or anorectic agents is exemplified by the following list: phenylpropanolamine, ephedrine, pseudoephedrine, phentermine, a cholecystokinin A (hereinafter referred to as CCK-A) agonist, a monoamine reuptake ( reuptake) inhibitor (such as sibutramine), a sympathomimetic agent, a serotonergic agent (such as dexfenfluramine, fenfluramine, or a 5-HT2C agonist such as BVT.933 or APD356, or duloxetine), a dopamine agonist (such as bromocriptine or pramipexole), a
  • anorectives include bombesin agonists, dehydroepiandrosterone or its analogs, glucocorticoid receptor agonists and antagonists, orexin receptor antagonists, urocortin binding protein antagonists, agonists of the glucogon-like peptide-1 receptor, such as exendin, AC 2993, CJC-1131, ZP10 or GRT0203Y, DPPIV inhibitors and ciliary neurotrophic factors, such as axokines.
  • therapies should be mentioned in this context, which lead to weight loss by increasing the fatty acid oxidation in peripheral tissue, such as inhibitors of acetyl-CoA carboxylase.
  • Agents for the treatment of hypertension include inhibitors of angiotensin converting enzyme, calcium antagonists, potassium channel openers, angiotensin II antagonists.
  • Inhibitors of the angiotensin converting enzyme include captopril, enalapril, alacepril, delapril (hydrochloride), lisinopril, imidapril, benazepril, cilazapril, temocapril, trandolapril, manidipine (hydrochloride).
  • calcium antagonists examples include nifedipine, amlodipine, efonidipine, nicardipine.
  • Potassium channel openers include Levcromakalim, L-27152, AL0671, NIP-121.
  • Angiotensin II antagonists include telmisartan, losartan, candesartan cilexetil, valsartan, irbesartan, CS-866, E4177.
  • HMG-CoA reductase inhibitors include pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, lipantil, cerivastatin, itavastatin, ZD-4522 and their salts.
  • Fibrate compounds include bezafibrates, clinofibrates, clofibrates, simfibrates.
  • Agents for the treatment of dyslipidemia, including arteriosclerosis include e.g. Drugs that increase HDL spotting, such as Nicotinic acid and its derivatives or preparations, such as Niaspan, and agonists of the nicotinic acid receptor.
  • Drugs that increase HDL spotting such as Nicotinic acid and its derivatives or preparations, such as Niaspan, and agonists of the nicotinic acid receptor.
  • Agents for the treatment of arthritis include NSAIDs (non-steroidal antiinflammatory drugs), in particular COX2 inhibitors such as meloxicam or ibuprofen.
  • Agents for the treatment of anxiety include chlordiazepoxides, diazepam, oxazolam, medazepam, cloxazolam, bromazepam, lorazepam, alprazolam, fludiazepam.
  • Agents for the treatment of depression include fluoxetine, fluvoxamine, imipramine, paroxetine, sertraline.
  • the dose for these active substances is expediently 1/5 of the usually recommended lowest dosage up to 1/1 of the normally recommended dosage.
  • the invention also relates to the use of at least one alkyne compound according to the invention and / or a salt according to the invention for influencing the eating behavior of a mammal.
  • This use is based in particular on the fact that compounds according to the invention may be suitable for reducing hunger, curbing appetite, controlling eating behavior and / or inducing satiety.
  • the eating behavior is favorably influenced so that the food intake is reduced. Therefore, the compounds of the invention find advantageous application for reducing body weight.
  • Another use of the invention is to prevent an increase in body weight, for example, in people who have previously taken weight-loss measures and are subsequently interested in maintaining the reduced body weight. In accordance with this embodiment, it is preferably a non-therapeutic use.
  • Such a non-therapeutic use may be a cosmetic application, for example, for altering the appearance or an application for improving the general condition.
  • the compounds according to the invention are preferably used non-therapeutically for mammals, in particular humans, who have no diagnosed disorders of eating behavior, no diagnosed obesity, bulimia, diabetes and / or no diagnosed micturition disorders, in particular urinary incontinence.
  • the compounds of the invention are suitable for non-therapeutic use in humans whose body mass index (BMI), defined as the kilogram of body weight divided by height (in meters) squared, is below the value of 30, in particular below 25, lies.
  • BMI body mass index
  • R r values are determined using blank TLC plates Kieselgel 60 F254 (E. Merck, Darmstadt, Article No. 1.05714) with no chamber saturation.
  • the R r values determined under the name Alox are determined using TLC plates alumina 60 F254 (E. Merck, Darmstadt, Article No. 1.05713) without chamber saturation.
  • silica gel from Millipore (MATREX TM, 35-70 my) or Alox (E. Merck, Darmstadt, aluminum oxide 90 standardized, 63-200 ⁇ m, article no: 1.01097.9050) is used.
  • the ratios indicated for the flow agents relate to volume units of the respective solvents.
  • volume units indicated for NH 3 solutions refer to a concentrated solution of NH 3 in water.
  • the acid, base and salt solutions used in the workups of the reaction solutions are aqueous systems of the stated concentrations.
  • AD-Mix-Alpha (article number: 39,275-8) and “AD-Mix-Beta” (article number: 39,276-6).
  • HPLC data are measured under the following parameters:
  • Preparative column Zorbax column (Agilent Technologies), SB (stable bond) C18; 3.5 ⁇ m; 30x
  • Preparative HPLC purifications generally use the same gradients used in the collection of analytical HPLC data.
  • the collection of products is mass-controlled, the product-containing fractions are combined and freeze-dried.
  • ⁇ * denotes the binding site of a residue
  • AD-Mix-Beta 43.80 g of AD-Mix-Beta are initially charged in 3 l of tert-butanol / water (1: 1) and stirred at RT for 20 min. The mixture is cooled to 0 ° C, 2.97 g (31.25 mmol) of methanesulfonamide and 7.54 g (31.25 mmol) of 1-benzyl-4-trifluoromethyl-1, 2,3,6-tetrahydropyridine are added, the cooling bath removed and 8 d stirred at RT. Another 22g of AD-Mix Beta and 1.5g Methanesulfonamide are added and stirred again at RT for 7 d. 11.2 g of natrium sulfite are added and stirred for 1 h.
  • Catalyst is filtered off and the filtrate i. vac. concentrated.
  • the product is obtained analogously to A3b starting from 5.0 g (26.7 mmol) of 1-benzyl-4-methyl-1,2,3,6-tetrahydropyridine and AD-Mix-Beta.
  • the product is obtained analogously to A3b starting from 7.5 g (40.0 mmol) of 1-benzyl-5-methyl-1,2,3,6-tetrahydropyridine and AD-Mix-Alpha.
  • the product is obtained analogously to Alb starting from 143 g (614 mmol) of 1-benzyl-4-ethylpyridinium chloride.
  • the product is obtained analogously to A3b starting from 14.37 g (71.4 mmol) of 1-benzyl-4-ethyl-1,2,3,6-tetrahydropyridine and AD-Mix-Beta.
  • the product can be obtained analogously to Ald starting from (3S, 4R) -1-benzyl-4-ethyl-piperidine-3,4-diol.
  • the product is obtained analogously to A3b starting from 4.0 g (25.1 mmol) of 1-benzyl-2,5-dihydro-1H-pyfrole and AD-Mix-Beta.
  • A8c cis-pyrrolidine-3,4-diol The product is obtained analogously to Ald starting from 0.97 g (5.04 mmol) of cis-1-benzylpyrrolidine-3,4-diol.
  • A11 a 1 -Benzyl-4-hydroxymethylpiperidin-4-ol The product is obtained analogously to A3b starting from 3.15 g (16.83 mmol) of 1-benzyl-4-methylene-piperidine and AD-Mix-Alpha.
  • A12b (S) -1-pyrrolidin-2-yl-cyclopropanol The product is prepared analogously to Ald starting from 745 mg (3.43 mmol) of 1 - ((S) -1-benzyl-pyrrolidine.
  • the product containing fractions are i.vac.
  • the residue was stirred with 20 mL EtOAc and 10 mL saturated NaHCO 3 solution, the organic phase separated and dried over Na 2 SO 4 . After removal of the drying agent and solvent, the residue is stirred with DIPE, filtered off with suction and dried.
  • Example 1.15b The product is prepared analogously to Example 1.15b starting from 70 mg (0.168 mmol) (2- ⁇ 4- [5- (4-chloro-phenyl) -pyridin-2-yiethynyl] -2-methylphenoxy ⁇ -ethyl) - cyclopropylmethyl-amine and 0.28 mL (3.35 mmol) of (S) -3-chloropropane-1,2-diol.
  • reaction mixture is purified by HPLC without working up.
  • the fractions containing the product are combined, to about 10 mL i.vac. concentrated, made alkaline with 5% NaHCO 3 solution and extracted with 20 ml of hot EtOAc.
  • the organic phase is separated and dried over Na 2 SO 4 .
  • Methanesulfonic acid 2- ⁇ 4- [5- (4-chloro-phenyl) -pyridin-2-yl-ethynyl] -phenoxy ⁇ -ethyl ester and 2.02 ml (20.0 mmol) of C-cyclopropyl-methylamine were prepared.
  • Example 1.19a The product is prepared analogously to Example 1.19a starting from 1.71 g (4.0 mmol) of methanesulfonic acid 2- ⁇ 4- [5- (4-chloro-phenyl) -pyridin-2-yl-ethynyl] -phenoxy ⁇ -ethyl ester and 0.54 g (4.8 mmol) of 1-aminomethyl-cyclopropanol.
  • the product is prepared analogously to Example 2.14b, starting from 83.8 mg (0.2 mmol) of 1 - [(2- ⁇ 4- [5- (4-chloro-phenyl) -pyridin-2-yl-ethynyl] -phenoxy ⁇ -ethyl-amino) -methyl ] -cyclopropanol and 37 ⁇ L (0.4 mmol) of tetrahydropyran-4-one.
  • reaction solution is added to a solution of 552 mg (14.62 mmol) of NaBH 4 in 5 ml of water so that the temperature does not exceed 30 ° C.
  • the mixture is stirred for 2 h at RT, added carefully with KHSO 4 solution until acidic reaction, basic with saturated Na 2 CO 3 - solution, extracted exhaustively with DCM, washed the combined organic phases twice with water and dried over MgSO 4 . After removal of the drying agent and solvent, the residue is triturated with PE, filtered off with suction and dried in air.
  • the diazonium salt formed is filtered off, washed with cold water, isopropanol and diethyl ether and concentrated in a desiccator i. vac. dried.
  • PE 100-140 ° C
  • the diazonium salt is added in portions and the mixture is stirred until no gas evolution can be observed.
  • the reaction mixture is cooled to RT, made alkaline with saturated Na 2 CO 3 solution and the aqueous phase is exhaustively extracted with MTBE.
  • the combined organic phases are washed with saturated Na 2 CO 3 solution and water, dried over MgSO 4 and i. vac. concentrated.
  • the residue is dissolved in DCM, filtered through silica gel and the filtrate i. vac. concentrated.
  • the product is prepared analogously to Example 4f starting from 60 mg (0.135 mmol) of methanesulfonic acid 2- ⁇ 4- [5- (4-chloro-phenyl) -3-fluoro-pyridin-2-yl-ethynyl] -phenoxy ⁇ -ethylester and 35.3 mg (0.269 mmol) of (3R, 4S) -4-methyl-piperidine-3,4-diol (amine A3).
  • the product is prepared analogously to Example 4f starting from 60 mg (0.135 mmol) of methanesulfonic acid 2- ⁇ 4- [5- (4-chloro-phenyl) -3-fluoro-pyridin-2-yl-ethynyl] -phenoxy ⁇ -ethylester and 34.2 mg (0.269 mmol) of (S) -1-pyrrolidin-2-yl-cyclopropanol (amine A12).
  • the product is prepared analogously to Example 4f starting from 60.0 mg (0.114 mmol) of methanesulfonic acid 2- ⁇ 2-bromo-4- [5- (4-chloro-phenyl) -3-fluoro-pyridin-2-yl-ethynyl] -phenoxy ⁇ - ethyl ester and 29.1 mg (0.229 mmol) of (S) -1-pyrrolidin-2-yl-cyclopropanol (amine A12).
  • Example 1a The product is prepared analogously to Example 1a starting from 10 g (42.7 mmol) of 4-iodo-2-methylphenol.
  • Example 5e The product is reacted analogously to Example 5e starting from 1.5 g (5.39 mmol) of 2- (4-iodo-2-methylphenoxy) ethanol and 1.25 g (5.39 mmol) of 5- (4-chlorophenyl) -2-ethynyl 3-fluoro-pyridine.
  • lithium aluminum hydride solution in 20 mL THF is a solution of 1.0 g (4.71 mmol) of 3- (5-bromo-pyridin-2-yl ) -prop-2-yn-1-ol in 5 mL THF is added dropwise so that the temperature does not exceed 0 ° C. After completion of the addition, stirring is continued for 2 h at 0 ° C. Excess lithium aluminum hydride is decomposed by careful addition of 0.13 mL water, 0.13 mL 15% NaOH, and 0.38 mL water. The precipitate is filtered and the organic phase dried over MgSO 4 .
  • reaction solution is stirred at 0 ° C. for a further 30 min and at RT overnight.
  • the reaction mixture is mixed with 50 mL of half-saturated NaHCO 3 solution, extracted exhaustively with DCM, the combined organic phases are washed twice with water and dried over MgSO 4 . After removal of the drying agent and solvent, the residue is reacted further without purification.
  • test methods for determining MCH receptor antagonist activity for example via the inhibition of the MCH receptor-mediated inhibition of cAMP production, as described by Hoogduijn M et al. in "Melanin-concentrating hormone and its receptor are expressed and functional in human skin", Biochem. Biophys. Res Commun. 296 (2002) 698-701 and on the biosensing measurement of the binding of MCH to the MCH receptor in the presence of antagonistic substances by piasmon resonance, as described by Karlsson OP and Lofas S.
  • Test cell hMCH-1 R stably transfected in CHO / Galpha16 cells. Results: IC50 values
  • Membranes from human hMCH-1R stably transfected CHO / Galpha16 cells are resuspended by syringe (0.6 x 25 mm needle) and assay buffer (50 mM HEPES, 10 mM MgCl 2 , 2 mM EGTA, pH 7.00, 0.1%).
  • Non-specific binding is defined as bound radioactivity in the presence of 1 micromolar MCH during the incubation period.
  • Unlabeled MCH competes with labeled 125 I-MCH for receptor binding with an IC50 value between 0.06 and 0.15 nM.
  • the KD value of the radioligand is 0.156 nM.
  • Test Cells Stably-transfected CHO / Galpha 16 cells with hMCH-R1
  • HBSS (10x) (GIBCO) HEPES Buffers M) (GIBCO)
  • Pluronic F-127 (Molecular Probes) Fiuo-4 (Molecular Probes) Probeside (Sigma)
  • MCH Bovine Serum Albumin
  • Serva (Protease Free)
  • DMSO DMSO
  • Ham's F12 BioWhittaker
  • FCS BioWhittaker
  • L-Glutamine GBCO
  • Hygromycin B GIBCO
  • PENStrep BioWhittaker
  • Clonal CHO / Galpha16 hMCH-R1 cells are cultured in Ham's F12 cell culture medium (with L-glutamine; BioWhittaker; Cat. No .: BE12-615F). This contains per mL mL 10% FCS, 1% PENStrep, 5 mL L-Glutamine (200 mM stock solution), 3 mL Hygromycin B (50 mg / mL in PBS) and 1.25 mL Zeocin (100 ⁇ g / mL stock solution).
  • the cells are plated on 384-well microtiter plate (black-walled with transparent bottom, manufacturer: Costar) at a density of 2500 cells per well and in the above-described medium overnight at 37 ° C, 5% CO 2 and 95% relative humidity cultured.
  • the cells are incubated with cell culture medium to which 2 mM Fluo-4 and 4.6 mM sampleicid are added at 37 ° C for 45 minutes. After loading with fluorescent dye, the cells are washed four times with Hanks buffer solution (1 ⁇ HBSS, 20 mM HEPES) supplemented with 0.07% Probenicid.
  • the test substances are diluted in Hanks buffer solution, mixed with 2.5% DMSO.
  • the background fluorescence of unstimulated cells is measured in the presence of substance in the 384-well microtiter plate five minutes after the last wash in the FLIPR 384 device (Molecular Devices, excitation wavelength: 488 nm, emission wavelength: bandpass 510 to 570 nm).
  • MCH is diluted in Hanks buffer with 0.1% BSA, pipetted 35 minutes after the last wash step to the 384-well cell culture plate and the MCH-stimulated fluorescence subsequently measured in the FLIPR 384 device.
  • the compounds according to the invention exhibit an MCH receptor antagonistic action in the abovementioned tests.
  • active ingredient denotes one or more compounds according to the invention, including their salts.
  • active ingredient also includes the other active substances.
  • 1 capsule for powder inhalation contains:
  • the active substance is ground to the particle size required for inhalation.
  • the ground active substance is mixed homogeneously with the milk sugar.
  • the mixture is filled into hard gelatin capsules.
  • 1 hub contains:
  • the active substance and benzalkonium chloride are dissolved in water and filled into Respimat® cartridges.
  • Inhalation solution for nebulizers containing 1 mg active substance Composition 1 vial contains:
  • Example D Propellant gas metered dose inhaler with 1 mq active substance Composition: 1 Stroke contains: active substance 1.0 mg lecithin 0.1% propellant ad 50.0 ⁇ l
  • micronised active substance is homogeneously suspended in the mixture of lecithin and propellant gas.
  • the suspension is filled into a pressure vessel with metering valve.
  • active substance 1.0 mg sodium chloride 0.9 mg benzalkonium chloride 0.025 mg disodium edetate 0.05 mg water purified ad 0.1 ml
  • Method of preparation The active ingredient and the excipients are dissolved in water and filled into a corresponding container.
  • Example F Injection solution with 5 mg of active substance per 5 ml Composition: active ingredient 5 mg glucose 250 mg human serum albumin 10 mg glykofurol 250 mg water for injections ad 5 ml production:
  • Glykofurol and glucose in water for injection dissolve (Wfl); Add human serum albumin; Dissolve active ingredient with heating; fill with Wfl to batch volume; Fill into ampoules under nitrogen fumigation.
  • Disodium hydrogenphosphate Na 2 HPO 4-2H ⁇ 2 mg
  • Dissolve polysorbate 80 sodium chloride, monopotassium dihydrogen phosphate and disodium hydrogen phosphate in water for injections (Wfl); Add human serum albumin; Dissolve active ingredient with heating; fill with Wfl to batch volume; fill in ampoules.
  • Dissolve mannitol in water for injections Wfl
  • Wfl water for injections
  • Human serum albumin Dissolve active ingredient with heating
  • fill with Wfl to batch volume to fill in vials; freeze-dry.
  • Polysorbate 80 Tween 80 20 mg Mannitol 200 mg
  • Example K suppository with 50 mg active substance Composition: Active substance 50 mg
  • Dissolve active ingredient with heating fill with Wfl to batch volume; Fill into ampoules under nitrogen fumigation.

Abstract

L'invention concerne des composés d'alcyne de formule générale (I), dans laquelle les groupes et les radicaux A, B, W, X, Y, Z, R<1> et R<2> ont la signification indiquée dans la revendication 1. L'invention concerne en outre des médicaments contenant au moins une alcyne selon l'invention. En raison de l'effet antagoniste de ces composés vis-à-vis du récepteur MCH, les médicaments selon l'invention sont appropriés pour le traitement de troubles métaboliques et/ou de troubles nutritionnels, notamment de l'adiposité et du diabète.
EP05716558A 2004-04-14 2005-04-08 Nouveaux composes d'alcyne a effet antagoniste vis-a-vis de mch et medicaments contenant ces composes Withdrawn EP1740572A1 (fr)

Applications Claiming Priority (2)

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DE102004017935A DE102004017935A1 (de) 2004-04-14 2004-04-14 Neue Alkin-Verbindungen mit MCH-antagonistischer Wirkung und diese Verbindungen enthaltende Arzneimittel
PCT/EP2005/003683 WO2005103031A1 (fr) 2004-04-14 2005-04-08 Nouveaux composes d'alcyne a effet antagoniste vis-a-vis de mch et medicaments contenant ces composes

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TW (1) TW200602025A (fr)
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US7452911B2 (en) 2002-10-31 2008-11-18 Boehringer Ingelheim Pharma Gmbh & Co. Kg Alkyne compounds with MCH antagonistic activity and medicaments comprising these compounds
DE102004017934A1 (de) * 2004-04-14 2005-11-03 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue Alkin-Verbindungen mit MCH-antagonistischer Wirkung und diese Verbindungen enthaltende Arzneimittel
DE102004017930A1 (de) * 2004-04-14 2005-11-03 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue Alkin-Verbindungen mit MCH-antagonistischer Wirkung und diese Verbindungen enthaltende Arzneimittel
KR20090047542A (ko) 2006-08-25 2009-05-12 베링거 인겔하임 인터내셔날 게엠베하 Ｍｃｈ 길항 활성을 갖는 신규한 피리돈 유도체 및 당해 화합물을 포함하는 의약
TW200831485A (en) 2006-12-11 2008-08-01 Boehringer Ingelheim Int New pyridazine derivatives with MCH antagonistic activity and medicaments comprising these compounds

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US5856510A (en) * 1996-12-16 1999-01-05 Allelix Biopharmaceuticals Inc. 5-alkenyl and 5-alkynyl indole compounds
TW544448B (en) * 1997-07-11 2003-08-01 Novartis Ag Pyridine derivatives
CA2386474A1 (fr) * 1999-09-20 2001-03-29 Takeda Chemical Industries, Ltd. Antagoniste de l'hormone de concentration de la melanine
DE10250708A1 (de) * 2002-10-31 2004-05-19 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue Alkin-Verbindungen mit MCH-antagonistischer Wirkung und diese Verbindungen enthaltende Arzneimittel
DE102004017934A1 (de) * 2004-04-14 2005-11-03 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue Alkin-Verbindungen mit MCH-antagonistischer Wirkung und diese Verbindungen enthaltende Arzneimittel
DE102004017930A1 (de) * 2004-04-14 2005-11-03 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue Alkin-Verbindungen mit MCH-antagonistischer Wirkung und diese Verbindungen enthaltende Arzneimittel

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CA2559021A1 (fr) 2005-11-03
DE102004017935A1 (de) 2005-11-03
WO2005103031A1 (fr) 2005-11-03
TW200602025A (en) 2006-01-16
AR048692A1 (es) 2006-05-17

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